ES2402961T3 - Bone replacement material - Google Patents

Abstract

Biphasic calcium phosphate / hydroxyapatite (CAP / HAP) bone substitute material comprising a sintered CAP core and at least a uniform and closed epittactically grown layer of nanocrystalline HAP deposited on top of the CAP core, so that the epittactically growing nanocrystals have the same size and morphology than human bone mineral, that is, a length of 30 to 46 nm and a width of 14 to 22 nm.

Description

Bone replacement material

The invention relates to a new biphasic bone substitute material with a bilayer structure based on calcium phosphate / hydroxyaparite (CAP / HAP), a method for preparing that material and its use as an implant or prosthesis to support bone formation, bone regeneration, bone repair and / or bone replacement at a defective site in a human or animal being.

Defects in a bone structure start from a variety of circumstances, such as trauma, disease and surgery is still a necessity for the effective repair of bone defects in various surgical fields.

To stimulate healing at the site of a bone defect, numerous natural and synthetic materials and compositions have been used. A well-known natural and osteoconductive bone substitute material that promotes bone growth in periodontal and maxillofacial bone defects is Geistlich Bio-Oss®, commercially available from Geistlich Pharma AG. This material is manufactured from natural bone by a procedure described in US Patent No. 5,167. 961, which allows the conservation of the trabecular structure and the nanocrystalline structure of natural bone, resulting in an excellent osteoconductive matrix that is not resorbed or that is resorbed very slowly.

Tricalcium phosphate / hydroxyapatite (TCP / HAP) systems and their use as bone substitute materials are described in, for example, US Patent 6,338,772 which discloses a process for preparing a biphasic cement of (-TCP / HAP by heating a powder mixture of ammonium phosphate and PAH at 1200-1500 ° C.

European patent EP-285826 describes a process for the production of a layer of PAH on metallic and nonmetallic bodies for implants by applying a layer of (-TCP and completely converting the layer of (-TCP in PAH by reaction with water of pH 2 at 7 at 80-100 ° C. The product obtained is a metallic or non-metallic body coated with a layer of PAH.

WO 97/41273 describes a process for coating a substrate, such as notably hydroxyapatite (PAH) or other calcium phosphates (CAP), with a carbonated hydroxyapatite coating, that is, hydroxyapatite in which phosphate and / or hydroxyl ions are partially replaced. by bicarbonate ions, by a process comprising (a) submerging the substrate in a solution at pH 6.8-8.0 containing calcium ions, phosphate ions and bicarbonate ions at a temperature below 50 ° C, (b) heating a portion of the solution in contact with the substrate at a temperature of 50 to 80 ° C having a pH greater than 8, (c) keeping the substrate in contact with the alkaline solution obtained in step (b) to form a carbonated hydroxyapatite coating and (d) extract the substrate from the solution and subject the coating to drying. It is indicated that the bicarbonate ions act as inhibitors of the growth of hydroxyapatite crystals, resulting in non-stoichiometric crystals that contain defects and have rather small dimensions, namely 10-40 nm in length and 3-10 nm in width (see p. 7, lines 1-7).

The components of calcium phosphate / hydroxyapatite (CAP / HAP) systems, especially TCP / HAP systems, differ in terms of their thermodynamic stability. Due to this difference, when CAP / HAP systems are implanted in a mammal, in space a human being, the solubility of TCP and other calcium phosphates is greater in the body fluid than the solubility of HAP. The difference in solubility between calcium phosphates and PAH causes the disruption of the disordered sintered structure of the CAP / PAH system because the more soluble CAP compound (for example, TCP) is eliminated more rapidly than PAH. The sintered interconnection between CAP and PAH produced at high temperatures will also contribute significantly to the greater solubility of the device in the physiological environment. Two different types of reactions dominate the accelerated in vivo degradation of such ceramics: chemical dissolution and biological resorption by cells. Both processes cause the dissolution of the ceramic material that also causes a local supersaturation of calcium ions, so there are more calcium ions released than adsorbed calcium ions. The natural balance of calcium ions no longer exists, neither in the extracellular matrix nor in the tissue surrounding the implant. The local alteration of the natural calcium balance in terms of supersaturation of calcium ions leads to an intensified osteoclastic activity and, therefore, to a poorly controlled resorption of the ceramic material and a risk of adverse inflammation, especially when large amounts of synthetic material are used bone substitute

When the Geistlich Bio-Oss® bone substitute material is implanted in a human patient, the natural calcium balance is practically not affected, the concentration of calcium ions being almost constant on the surface of the material and within its local environment. Therefore, the biological resorption of the material does not take place or takes place at a very slow speed without risk of adverse inflammation reactions.

The aim of the present invention is to provide a bone substitute calcium phosphate / hydroxyapatite (CAP / HAP) material, as a Geistlich Bio-Oss® bone substitute material, which, after applied in vivo, allows the concentration of bone to remain constant. Calcium ions on the surface of the material and within your local environment and do not lead to increased osteoclastic activity.

The natural calcium balance that is necessary for optimal bone regeneration should not be altered or destroyed. In addition, the natural balance of calcium concentration must be endured by the bone substitute material until the regeneration process is complete. When these conditions are satisfied, there is no increase in osteoclastic activity and, therefore, there is no risk of adverse inflammation reactions.

It has been found that the stated objective is achieved with a new biphasic nanocrystalline material of CAP / PAH, bone substitute, with a biomimetic structure of exactly defined bilayer obtained under specific conditions described here.

Indeed, as the observation by fluorescent light microscopy of that bone replacement CAP / HAP material implanted in a mammal reveals, there is no detectable increase in osteoclast activity in the vicinity of the implant, indicating the absence of an increase in the concentration of calcium ion on the surface of the material and within its local environment.

The new biphasic nano-crystalline CAP / HAP bone replacement material shows very interesting in vivo properties.

The invention thus relates to a biphasic calcium phosphate / hydroxyapatite (CAP / HAP) bone substitute material comprising a sintered CAP core and at least a closed and epittatically grown uniform layer of nanocrystalline PAH, deposited on top of the sintered CAP core , so that epitactically grown nanocrystals have the same size and morphology as the human bone mineral, that is, a length of 30 to 46 nm and a width of 14 to 22 nm.

The sintered CAP core may comprise tricalcium phosphate (TCP), notably (-TCP ((-Ca3 (PO4) 2) or l-TCP (l-Ca3 (PO4) 2) and / or tetracalcium phosphate (TTCP) Ca4 (PO4 ) 2O.

According to a frequently used embodiment, the sintered CAP is essentially constituted by TCP, with preference (-TCP.

The epittactically grown layer of nanocrystalline PAH is structurally and chemically almost identical to the natural human bone mineral.

The epittactically grown layer of nanocrystalline PAH generally has a thickness of at least 15 to 50 nm, preferably at least 20 to 40 nm, more preferably at least 25 to 35 nm. The minimum thickness corresponds to a layer of PAH nanocrystals in epitaxial orientation.

The epittactically grown layer of nanocrystalline PAH may comprise a layer or multiple layers of PAH nanocrystals in epitaxial orientation. The thickness of the epittactically grown layer of nanocrystalline PAH, which is related to the number of such PAH nanocrystals in epitaxial orientation, will be selected according to the intended application of bone substitute material as an implant or prosthesis in differently charged body parts, The bone substitute material of the invention is designed to function as an in vivo system that progressively transforms the sintered CAP nucleus into hydroxyapatite of similar size and morphology to those of the human bone mineral, depending on the speed of that release transformation. of calcium by the sintered CAP core, which is largely controlled by the thickness of the epittactically grown nanocrystalline HAPA layer.

The properties of the CAP / HAP bone substitute material are controlled to a large extent by the thickness of the epitactic-grown crystalline PAH layer. The term "properties" includes the ability of the CAP / HAP bone substitute to release a constant concentration of calcium ions to the local medium in vitro and in vivo.

The thickness of the epitactically grown nanocrystalline HAP layer is related to the ratio of the sintered CAP core material to PAH, a ratio that is generally between 5:95 and 95: 5, preferably from 10:90 to

90:10

The CAP / HAP bone substitute material may be in the form of particles or as granules, particles or granules having the desired size and shape. Generally, the particles or granules are approximately spherical and have a diameter of 250 to 5000 µm.

The CAP / HAP bone substitute material may also be a shaped body, for example, a screw, a nail, a pin or a structure having the profile of a bone body piece such as notably a hip, a clavicle, a rib, a jaw, a part of the skull. Such a screw, nail or pin can be used in reconstructive orthopedic surgery to fix a ligament to a bone, for example, in the knee or elbow. Such a structure that has the profile of a piece of a bone body can be used in orthopedic surgery as a prosthesis to replace a missing or defective bone or piece of bone.

The invention further relates to a process for preparing said CAP / HAP bone substitute material, which comprises the steps of:

(to)

 prepare a sintered CAP core material,

(b)

 immerse the sintered CAP core material in an aqueous solution at a temperature between 10 ° C and 50 ° C to initiate the CAP transformation process in PAH, whereby, on the surface of the sintered CAP core material, a uniform layer is formed and closed grown epitactically, having epittactically grown nanocrystals the same size and morphology as the human bone mineral,

(C)

stop the transformation by separating the material from the aqueous solution at the moment in which there is a uniform and closed coating of at least one nanocrystalline layer of PAH, but before the transformation process is completely completed,

(d)

 optionally, sterilize the separated material from step (c).

The sintered CAP core material may comprise tricalcium phosphate, notably (-TCP ((-Ca3 (PO4) 2) or l-TCP (l-Ca3 (PO4) 2) and / or tetracalcium phosphate (TTCP) Ca4 (PO4) 2O.

According to a frequently used embodiment, the sintered CAP core material consists essentially of TCP, with preference (-TCP.

The preparation of the sintered CAP core material can be carried out by methods known in the art that comprise mixing calcium hydrogen phosphate (CaHPO4) 2 powders, calcium carbonate and / or calcium hydroxide first, then calcining the mixture within an appropriate temperature range , resulting in a bulk sintered CAP core material (see, for example, Mathew M et al., 1977, Acta Cryst. B33: 1325; Dickens B. et al., 1974, J. Solid State Chemistry 10, 232 ; and Duracan C. et al., 2002, J. Mat. Sci., 37: 963).

A bulk sintered TCP core material can thus be obtained by mixing calcium hydrogen phosphate powders (CaHPO4), calcium carbonate and / or calcium hydroxide in stoichiometric ratio, calcining and sintering the mixture at a temperature in the range of 1200-1450 ° C, preferably at about 1400 ° C ...

A bulk sintered TCP core material can therefore also be obtained by the procedure described above.

The bulk sintered CAP material prepared by such procedures can be porous with a porosity of 12 to 80% and a wide distribution of the pores. Porosity parameters will be selected according to the intended application of the CAP / HAP bone substitute material.

The bulk sintered CAP material used in step (b) can be:

-

 bulk sintered CAP core material prepared as described above,

-

a particle sintered or granulated CAP core material obtained from bulk sintered CAP core material prepared as described above, using traditional methods such as crushing, crushing and / or grinding, and sieving, or

-

 a preform of sintered CAP core material having the desired shape and size, for example, a screw, a nail, a pin or a structure having the profile of a bone body piece.

Such a preform of any shapes and sizes can be obtained from the bulk sintered core material prepared as described above, using well known prototyping techniques such as CNC machining or 3D printing (eg Bartolo P. et al., 2009, Bio-Materials and Prototyping Applications in Medicine, Springer Science New York, ISBN 978-0-387-47682-7; Landers R et al., 2002, Biomaterials 23 (23), 4437; Yeong W.-Y et al., 2004, Trends in Biotechnology, 22 (12), 643; and Seitz H. et al., 2005, Biomed. Mat. Res. 74B (29; 782).

The aqueous solution of step (b) may be pure water, a simulated body fluid or a buffer. It is important that the pH value of the immersion solution of step (b) is almost neutral and that it remains stable throughout the transformation process, preferably in a pH range of 5.5 to 9.0.

The buffer may be any buffer in the pH range indicated above, but preferably it is a phosphate buffer with or without calcium, magnesium and / or sodium.

The term "simulated body fluid" refers to any solution that mimics a body fluid. Preferably, the simulated body fluid has an ion concentration similar to that of blood plasma.

The temperature range in step (b) is generally between 10 ° C and 50 ° C, preferably between 25 and 45 ° C, more preferably between 35 ° C and 40 ° C.

The immersion stage (b) induces in a first phase a first order transition of the CAP core material and, therefore, the nucleation of HAP nanocrystal precursors. During the second phase, the PAH precursors resulting from the first phase will grow and establish a closed layer (that is, completely coated) of epitactic nanocrystalline composite. The first layer of PAH nanocrystals must be uniform and closed and connected epitaxically to the sintered CAP core material.

During a third phase, the first order phase transition can take place within the newly formed bilayer composite material to transform the sintered CAP core material (TCP or TTCP) into nanocrystalline HAP. During this third stage of phase transition, calcium ions will be released for a time that can be controlled by a controlled slow diffusion process until a part of the sintered CAP core material has been transformed into nanocrystalline PAH. The transformation time and, therefore, the rate of calcium release can be controlled by varying the thickness of the HAP layer.

The epitactically grown nanocrystalline PAH layer, of an appropriate thickness, will be prepared in vitro, having previously stopped the transformation of CAP into PAH before it is complete.

As soon as the CAP / HAP bone substitute material is placed in vivo, the CAP transformation process in PAH will be reactivated by contact with body fluids and the bone substitute material will function as a live-type system that forms new hydroxyapatite. , similar in size and morphology to human bone mineral. During the in vivo phase transformation process, the transported released calcium ions will be released into the local medium that supports the local calcium balance, which is important and beneficial for bone regeneration processes.

Due to different regeneration times of bone defects in differently charged regions of the body, it is important that the rate of calcium release can be controlled. This can be achieved by varying the thickness of the epitactically grown hydroxyapatite layer.

Therefore, stage (c) is a very critical stage. The exposure time in the aqueous solution of step (b) is based on the thickness of the desired PAH layer. At least one layer of nanocrystalline PAH in epitaxial orientation is necessary. It is essential that the transformation of CAP into HAP has not been completed.

The appropriate exposure time according to the desired thickness can be calculated using several differential thermodynamic equations well known to a person skilled in the art of calcium phosphates and the chemistry of cement and concrete.

See, for example: Pommersheim, J.C, Clifton, J.R. (1979) Cem. Conc. Res., 9: 765; Pommersheim, J.C; Clifton,

J.R. (1982) Cem. Conc. Res, 12: 765; and Schlüssler, K.H. Mcedlov, O.P. (1990): Der Baustoff Beton, VEB Verlag Bauwesen, Berlin.

By transferring the solution of the aforementioned differential equations to the CAP / PAH system, the CAP transition in PAH and the thickness of the layer can be predicted, and the PAH epitactic layer can be prepared in a stable and reproducible manner.

The solid material is separated from the aqueous solution usually by filtration and drying using methods well known in the art.

The optional sterilization step (d) can be performed by methods well known in the art such as gamma irradiation.

The invention also concerns the use of the CAP / HAP bone substitute material defined above, generally in the form of a shaped body, as an implant or prosthesis to support bone formation, bone regeneration, repair and / or bone replacement in a defective site in a human or animal being.

The invention also relates to a method for promoting bone formation, bone regeneration and / or bone repair at a defective site of a human or animal implanting the CAP / HAP bone substitute material defined above, generally in the form of a particulate or shaped body.

Advantages of the CAP / HAP bone substitute material of the invention

The epitactically grown PAH nanocrystals surrounding the sintered CAP core material are of a size and morphology identical to the apatite crystals of natural human bone mineral, as shown in Table 1. Thus, the bone substitute material CAP / HAP of the invention successfully mimics the composite or microstructure of bone and is representative of biomimetic material of human bone mineral.

Table 1

Comparison of the size and morphology of PAH crystals for the CAP / PAH bone substitute of the invention and human bone mineral

Crystallographic axes (hexagonal space group P63 / m)

CAP / HAP of the invention prepared at physiological temperature Crystal size + [nm] Natural human bone mineral Crystal size * [nm]

a (1.0.0) b (0.1.0) c (0.0.1)

18 (+4) 18 (+4) 38 (+8) 15-21 15-21 34-45

* Crystal size analysis was performed using TEM (transmission electron microscopy), SPM (scanning microscopy techniques) as well as refining X-ray diffraction data using the Bragg method.

The constant concentration of calcium ions results in an improved adhesion of osteoblasts and osteoclasts to the surface of PAH in the correct relationship for osteogenesis and thus to a steady state in the bone regeneration cycle. A surface is provided on which osteoblasts and osteoclasts easily bind in the correct relationship for bone regeneration.

In addition, due to its highly controllable surface properties, the bone substitute CAP / HAP material of the invention can act as a matrix for bioactive molecules such as extracellular matrix proteins such as growth factors, notable for bone regeneration.

The following examples illustrate the invention without limiting its scope.

Example 1 Preparation of a bulk sintered (-TCP) material

For a mixture of 500 g (dry weight) they were mixed for 7 min at 500 rpm, using a laboratory stirrer, 360 g of anhydrous dicalcium phosphate, 144 g of potassium carbonate and 220 ml of deionized water. The suspension of the mixing process was immediately transferred to a stable high temperature platinum cup. The full platinum cup was put in a cold oven. The oven was heated at 1400 ° C at a heating rate of 60 ° C per hour. After 72 hours the heating process was stopped by disconnecting the oven. The bulk sintered material (phase of (-Ca3 (PO4) 2 pure) was taken out of the oven and the platinum vessel. The bulk product of the sintering process had a weight of 420 g (weight loss, 16.7% ).

The phase purity control was performed by powder X-ray diffraction analysis.

Example 2 Preparation of porous granules of (-TCP sintered with a particle size between 0.25 and 2 mm.

The bulk product of Example 1 was crushed using a jaw crusher (opening size 4 mm). The coarse granules were screened using a sieve insert sieve with a mesh opening of 2 mm and 0.25 mm. After screening, the granule fractions were rinsed 2 times with purified water to separate residual fine dust particles adsorbed to the granules. The porous granules were dried for 10 hours at 20 ° C in a dryer. The control of grain size distribution was done using laser diffraction technology. The cleaning of the surface of the particles after rinsing was monitored by observation of the surface by scanning electron microscopy.

Example 3 Preparation of porous cylinders (length 10 mm, diameter 6 mm) of (-TCP by CNC machining The bulk product of Example 1 was machined to a cubic piece whose edges were a = 3 cm, b = 2 cm, c = 2 cm using a cutting machine The piece was placed in a 4-axis CNC grinding machine equipped with a 3 mm diameter round head hard metal machining cutting tool.The cylinders were machined by helical grinding with a diameter of 3 mm and a slope of 0.25 mm The main speed of the workpiece during CNC grinding was 1700 rotations per minute, the maximum helical grinding speed was calculated by an integral procedure within the CNC equipment and 10 rotations averages per minute After grinding, the cylindrical preforms were rinsed twice with purified water to remove residual fine dust adsorbed to the cylindrical surface.The porous cylinders were dried at 120 ° C for 10 hours and n a closet dryer. The cleanliness of the preform surface after rinsing was monitored by examining the surface by scanning electron microscopy. The correction of the dimensions of the preform was controlled using a sliding gauge.

Example 4 Preparation of a coating of nanocrystalline PAH epitactically grown on the granules of (-TCP sintered from Example 2.

A buffered solution (1000 ml) suitable for the coating and transformation process was prepared using 1.82 mol / l of sodium, 4.68 mol / l of hydrogen, 0.96 mol / l of phosphorus, 5.64 mol / l of oxygen, 0.01 mol / l of calcium and 0.71 mol / l of chlorine. The pH of the solution was adjusted to 7.4 at a temperature of 40 ° C. The granules produced according to Example 1 and Example 2 were immersed in the prepared solution and stored in a good temperature water bath (40 ° C) for a time calculated according to a layer thickness at an average of 250 nm (10 hours) which is equivalent to a phase composition (w / w) of 75% (-TCP and 25% hydroxyapatite. After immersing them, the granules were rinsed 3 times with purified water to remove residuals from the buffered solution. The porous granules were dried for 4 hours at 120 ° C. in a cabinet dryer The phase composition of the granules was analyzed by Rietveld analysis of X-ray powder diffraction data, the size of the crystals of crystalline phases obtained by the Coating process was analyzed by refining size deformation of X-ray diffraction data according to the Bragg technique.The porosity of the granules was controlled using mercury intrusion porosimetry, l The surface morphology after coating was monitored using scanning electron microscopy.

Example 5 Preparation of a coating of epistactically grown nanocrystalline PAH on the sintered -TCP cylinders of Example 3

A buffered solution (1000 ml) suitable for coating and performing the phase transformation process was prepared using 1.82 mol / l of sodium, 4.68 mol / l of hydrogen, 0.96 mol / l of phosphorus, 5, 64 mol / l of oxygen, 0.01 mol / l of calcium and 0.71 mol / l of chlorine. The pH of the solution was adjusted to 7.4 at a temperature of 40 ° C. The porous cylinders produced according to Examples 1 and 3 were immersed in the prepared solution and stored in a good temperature water bath (40 ° C) for a time calculated according to a layer thickness at an average of 20 µm (60 hours) equivalent to a phase composition (w / w) of 85% of (-TCP and 15% (w / w) of hydroxyapatite. After immersing them, the cylinders were rinsed 3 times with purified water to remove the residuals of the buffered solution The porous cylinders were dried for 10 hours at 120 ° C. in a cabinet dryer The composition of the cylinder phases was analyzed by Rietveld analysis of the powder X-ray diffraction data, the sizes of the crystals of the phases obtained by the coating procedure were analyzed by size-strain refinement of X-ray diffraction data according to the Bragg technique Epitaxial growth was analyzed using difference spectroscopy of reactance (RD). The porosity of the cylinders was controlled using mercury intrusion porosimetry, the surface morphology after coating was controlled by scanning electron microscopy. The layer thickness was controlled using high energy electron diffraction by reflection (RED) and / or photoelectron spectroscopy (XPS).

Example 6 Influence of immersion time on layer thickness and phase composition

Tables 2 and 3 show experimental data for an example that shows the influence of immersion time on the layer thickness and phase composition, respectively, for particles of (-TCP porous with almost spherical geometry and size from 10 to 20! m, a porosity of 25-40% by volume, a specific surface (interior) of 50-60 m2 / g, an apparent density of 0.6-0.8 ml.

 Table 2

Influence of immersion time on the thickness of the layer

Immersion time

Layer Thickness *, nm

0 15 30 60 600

-37 (+10) 112 (+4) 121 (+9) 238 (+8)

* The epitaxy, the chemical composition of the layer and the analysis of the layer thickness were made by RED (high energy electron diffraction by reflection) and XPS () photoelectron spectroscopy.

 Table 3 Influence of immersion time on phase composition

Dive time, h

TCP **,% by weight PAH **,% by weight

0

100 -

0.5

86.6 (+1) 13.4 (+2)

one

85.8 (+1) 14.2 (+3)

2

83.5 (+1) 16.4 (+3)

5

78.1 (+1) 21.9 (+3)

7.5

75.3 (+1) 24.7 (+3)

10

74.2 (+5) 25.8 (+2)

12

58.8 (+6) 41.2 (+7)

24

44.8 (+9) 55.2 (+6)

48

35.8 (+6) 64.2 (+3)

72

- 100

** Quantitative phase analysis was performed using the Rietveld refining of powder X-ray diffraction data.

*** The experimental data were evaluated in a system with the following parameters: Liquid phase: PBS buffered saline liquid, 20x, temperature 40 ° C.

Claims (14)

one.

 Biphasic calcium phosphate / hydroxyapatite (CAP / HAP) bone substitute material comprising a sintered CAP core and at least a uniform and closed epittactically grown layer of nanocrystalline HAP deposited on top of the CAP core, so that the epittactically crecidis nanocrystals have the same size and morphology as the human bone mineral, that is, a length of 30 to 46 nm and a width of 14 to 22 nm.

2.

 A CAP / HAP bone substitute material according to claim 1, wherein the epittactically grown layer of nanocrystalline PAH generally has a thickness of at least 15 to 50 nm.

3.

 A CAP / HAP bone substitute material according to claim 1, wherein the epittactically grown layer of nanocrystalline PAH generally has a thickness of at least 20 to 40 nm.

Four.

 A CAP / HAP bone substitute material according to any one of claims 1 to 3, wherein the ratio of sintered CAP core material to PAH is between 5:95 and 95: 5.

5.

 A CAP / HAP bone substitute material according to any one of claims 1 to 3, wherein the ratio of sintered CAP core material to PAH is between 10:90 and 90:10.

6.

 A CAP / HAP bone substitute material according to any one of claims 1 to 5, wherein the sintered CAP core consists essentially of (-TCP.

7.

 A CAP / HAP bone substitute material according to any one of claims 1 to 6, which is a particulate material or a granulate.

8.

 A CAP / HAP bone substitute material according to any one of claims 1 to 6, which is a shaped body.

9.

 A shaped body of claim 8, which is a screw, a nail or a pin.

10.

 A shaped body of claim 8, which is a structure having the profile of a piece of bone body.

eleven.

 A process for preparing the CAP / HAP bone substitute material of any one of claims 1 to 10, comprising the steps of

(to)

 prepare a sintered CAP core material,

(b)

 immerse the sintered CAP core material in an aqueous solution at a temperature between 10 ° C and 50 ° C to initiate the process of transforming CAP into HAP whereby a uniform and closed layer grown on the sintered CAP core material will be formed epitactically of nanocrystalline hydroxyapatite, with the nanocrystals grown epittactically the same size and morphology as human bone mineral,

(C)

stop the transformation by separating solid material from the aqueous solution when a uniform and closed coating of at least one nanocrystalline layer of PAH is present, but before the transformation process is complete, and

(d)

 optionally, sterilize the separated material from step (c).

12.

A process of claim 11, wherein, in step (b), the pH of the aqueous solution remains within the range of 5.5 to 9.0.

13.

 A process of claim 11 or 12, wherein the temperature in step (b) is between 25 and 45 ° C, preferably between 35 ° C and 40 ° C.

14.

 A CAP / HAP bone substitute material according to any one of claims 1 to 10 for use as an implant or prosthesis for bone formation, bone regeneration, bone repair and / or bone replacement at a defective site of a human or animal